The abnormal pattern of visual evoked potentials in rabbits with hepatic encephalopathy (HE) due to fulminant hepatic failure (FHF) resembled that induced by barbiturates and benzodiazepines. As these drugs induce neural inhibition by interacting with receptors for the inhibitory neurotransmitter Gamma-aminobutyric acid on postsynaptic neural membranes, this finding implies that neuronal activity in HE is similar to that induced by GABA. Outside the CNS the main source of GABA is gut bacteria and the main site of its catabolism is the liver. When FHF was induced in rabbits the onset of HE was preceded by a marked increase in plasma GABA levels and by an increase in the permeability of the blood brain barrier (BBB). Scatchard plots of the specific binding of 3H-GABA to rabbit postsynaptic membranes indicated the presence of two independent receptors for GABA. FHF was associated with a twofold increase in the number of both receptors. These findings suggest that as the liver fails: 1) impaired hepatic metabolism of GABA leads to an increase of gut-derived GABA in plasma, 2) plasma GABA gains access to the brain through a permeable BBB and 3) plasma-derived GABA may induce its own receptors and thereby increase the sensitivity of the brain to GABA.